Dimethyl sulfoxide (dmso) and methylsulfonylmethane (msm) formulations to treat osteoarthritis

ABSTRACT

Embodiments of the invention relate generally to the use of formulations comprising DMSO and MSM to treat arthritis (such as osteoarthritis), pain, inflammation, and/or degeneration. DMSO and MSM formulations are administered orally and/or topically in several embodiments and provide effective treatment of both chronic and acute symptoms of arthritis (e.g., osteoarthritis), pain, inflammation, and/or degeneration. Solid forms of DMSO are provided in several embodiments.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/503,626, filed on Apr. 23, 2012, which is the U.S. National Phaseapplication under 35 U.S.C. §371 of International ApplicationPCT/US2010/054870, filed on Oct. 29, 2010, which claims the benefit ofU.S. Provisional Patent Application Nos. 61/256,935, filed on Oct. 29,2010; and 61/319,203, filed on Mar. 30, 2010, the disclosure of each ofwhich is expressly incorporated by reference herein.

BACKGROUND Field of the Invention

Embodiments of the invention relate generally to formulations comprisingdimethyl sulfoxide (DMSO) and/or methylsulfonylmethane (MSM) and the useof those compounds for the treatment of arthritis (such asosteoarthritis) and other conditions. Solid formulations comprisingDMSO, alone or in combination with MSM, are provided in severalembodiments.

Description of the Related Art

Cartilage is a protein matrix which functions to lubricate and cushionthe joints. Osteoarthritis, or degenerative arthritis, refers to a classof diseases and mechanical abnormalities that result in degradation ofjoints, structurally and therefore, functionally. The articularcartilage of joints and the juxtaposed subchondral bone (e.g., the endsof the bone) are frequently affected.

Clinically, osteoarthritis may present with symptoms such as joint painor minor tenderness of load bearing joints. Symptoms range from thislevel of “everyday aches and pains” to severe sensitivity of joints,stiffness, inflammation, creaking, and locking of joints.

Osteoarthritis is the most common form of arthritis in the UnitedStates, affecting nearly 27 million people, and is the leading cause ofchronic disability. Osteoarthritis is linked to approximately 25% ofvisits to primary care physicians, and about 50% of non-steroidalanti-inflammatory prescriptions. Thus, in its various stages,osteoarthritis accounts for an enormous burden on those who suffer fromthe disease, their family and caretakers, as well as the medicalcommunity.

Severe cases of osteoarthritis may require surgery to replace joints,remove bone fragments, reposition and/or fuse bones to increasestability and reduce pain. However, these surgeries are costly, areassociated with long recovery times, and in some cases do not lead tosignificant alleviation of symptoms.

Dimethyl sulfoxide (DMSO; (CH₃)₂(SO)) is a polar, aprotic solvent widelyused as a solvent. It is frequently used in various chemical andbiological reactions and as a cryoprotectant for cell storage. Thestrong unpleasant odor of DMSO, along with several undesired sideeffects, have adversely impacted the use of DMSO in medicalapplications.

Methylsulfonylmethane (MSM; (CH₃)₂SO₂₎), also known as dimethyl sulfone,is an organosulfur compound that is a metabolite of DMSO and certainsulfur-containing amino acids. MSM has been marketed primarily as adietary supplement.

SUMMARY

The etiology of osteoarthritis is varied, and includes hereditary,developmental, metabolic, and mechanical aspects that may lead to lossof cartilage. Ironically, the responses generated by the body (e.g.,immune and regrowth processes) may accelerate damage to the cartilage.For example, when bone surfaces lose cartilage, subchondral bone may beexposed, damaged, and regrown. However, regrowth may lead to excessiveproliferation of dense bone in central areas of cartilage loss, furtherexacerbating the cartilage loss. As a result, a person suffering fromprogressive osteoarthritis may experience increasing pain upon weightbearing, including walking and standing. Additionally, the decreasedmovement because of the pain may cause regional muscles to atrophy andreduce tension on ligaments, further compromising the functionality ofthe joint.

Several options for therapy are available currently for those afflictedwith osteoarthritis. Paracetamol (Tylenol®/acetaminophen) is commonlyused to treat osteoarthritis pain and has demonstrated roughlyequivalent benefit to ibuprofen. However, doses demonstrating effectivepain relief (˜4g/day) have been associated with alterations in liverfunction as well as gastrointestinal bleeding or renal damage when usedchronically.

Non-steroidal anti-inflammatory (NSAID) drugs may be prescribed for moresevere cases of osteoarthritis. This class of drugs acts by inhibitingthe formation of prostaglandins and may reduce both the pain andinflammation associated with osteoarthritis. These drugs, however, arealso associated with adverse events including increased gastrointestinalbleeding, stomach upset, cramping, diarrhea, and peptic ulcer. Some ofthese drugs, namely the cyclooxygenase-2 inhibitors, have been withdrawnfrom the market due to their elevated risk for cardiovascular disease.Several NSAIDS are available for topical use, though the therapeuticeffect is generally minimal and short lived.

Oral corticosteroids carry a high rate of adverse side effects andproduce limited symptomatic improvement, and therefore are not typicallyrecommended for osteoarthritis treatment. Injections of corticosteroidsinto the intra-articular space may provide acute (e.g., several weeks)relief of pain, but do not generally offer a long term therapeuticeffect.

Thus, there remains a need in the art for an effective treatment forosteoarthritis, particularly one that addresses both the chroniccondition of osteoarthritis as well as the acute symptoms associatedwith the illness. Accordingly, in several embodiments, formulationscomprising MSM and DMSO, individually or combined, are provided foreither oral or topical use, either alone or in combination, to provideefficacious relief of both chronic and acute symptoms of osteoarthritis,while inducing minimal, reduced, or no, side effects.

In several embodiments, formulations comprising DMSO and MSM,individually or combined, are formulated as solids. A solid form ofDMSO, alone or in combination with MSM is particularly surprising andbeneficial because, in some embodiments, the solid form is associatedwith less odor than the liquid form. In several embodiments, the solidform stays solid at room temperature (e.g., about 20° C. −23° C.). Inother embodiments, the solid form stays solid at temperatures up to 30°C., 45° C., 60° C., 75° C., 100° C., or higher. In some embodiments, thesolid form does not crystallize and/or lose its texture at temperaturesbelow room temperature, 25° C., 15° C., 10° C., 5° C., or lower. Inseveral embodiments, the solid form maintains its chemical stabilityand/or integrity (e.g., phase integrity) at a wide range oftemperatures, including but not limited to ranges between about 0° C. toabout 100° C., about 5° C. to about 50° C., about 10° C. to about 40°C., about 20° C. and about 30° C., and overlapping ranges thereof. Inseveral embodiments, the solid form maintains a similar consistency,e.g., maintains one or more of a hardness, firmness, density, texture,and/or viscosity that is at least 75%, 85%, 95% or 100% the same, over arange of temperatures from about 0° C. to about 100° C., about 5° C. toabout 50° C., about 10° C. to about 40° C., about 20° C. and about 30°C., and overlapping ranges thereof. In several embodiments, the additionof a coating to the solid form and/or a stabilizer increases thestability temperature stability range by at least 10%, 25%, 50% or more.In one embodiment, the solid form maintains its chemical stabilityand/or integrity (e.g., phase integrity) in a range from about 10° C. toabout 40° C. without a coating and about 0° C. to about 50° C. with acoating. Coatings include, but are not limited to, vegetable-basedcoatings, biopolymers, colloidal particles, multilayer emulsions,colloidosomes, or combinations thereof

In several embodiments, solid forms of DMSO, alone or in combinationwith MSM, are provided in the form of a capsule. In one embodiment, theuse of solidified DMSO reduces the odor typically associated with DMSO.In another embodiment, the use of solidified DMSO reduces thephysiological side effects typically associated with DMSO. In someembodiments, the formulations are consumed orally to treatosteoarthritis, while in some other embodiments, the formulations areapplied topically. In still other embodiments, both oral and topicalformulations are used. In several other embodiments, formulationscomprising DMSO and MSM, individually or combined, are formulated asliquids.

As used herein, the phrase “symptoms of osteoarthritis” shall be givenits ordinary meaning and shall include, but not be limited to, one ormore of the following: cartilage degeneration, degeneration ofsubchondral bone, joint pain, tenderness, stiffness, creaking, lockingof joints, inflammation, structural changes in the joint, swelling,diminished grip strength, bony enlargement, diminished range of motion,osteophyte (or spur) formation, and synovial irritation. Symptoms ofosteoarthritis can occur, for example, in the knee, toe, thumb, finger,ankle, spine, hip, shoulder or other joint.

In several embodiments, formulations comprising MSM, DMSO and/or acombination of MSM and DMSO, alone or with other colors, flavorings,additives, fillers, carriers, excipients, and/or therapeutics are usedto prevent and/or treat osteoarthritis and/or symptoms thereof,arthritis and/or symptoms thereof, inflammation, joint pain, and/orstructural changes of the joint.

In several embodiments, formulations comprising MSM, DMSO and/or acombination of MSM and DMSO, alone or with other carriers, flavorings,additives, fillers, carriers, excipients, and/or therapeutics are usedto prevent and/or treat the following conditions that are unrelated toan osteoarthritic etiology: tissue degeneration, pain (e.g., jointpain), and/or inflammation.

Due to its physical properties, DMSO exists as a liquid at roomtemperature, and is therefore typically utilized as a liquid. However,there is a long felt and as yet unmet need for a solid form of DMSO atroom temperature. For example, a solid form of DMSO is particularlyadvantageous because, in some embodiments, it can be provided as a pill,tablet or capsule, is suitable for concentrated dosages, and exhibitsreduced side effects as compared to a liquid form (e.g., lessirritation, sensitivities, gastrointestinal effects, etc.). In severalembodiments, solid forms offer controlled release in the body, and insome embodiments, are more slowly released and/or more effectivelyabsorbed. In one embodiment, a solid form that dissolves in a desiredarea (e.g., small intestine) is provided, thereby offering enhancedbioavailability based on targeted delivery. Further, solid forms of DMSOexhibit reduced or no odor as compared to the liquid form in someembodiments. Thus, several embodiments of the present invention providea formulation comprising DMSO that is solid at room temperature, andmethods of making same.

In several embodiments, formulations comprising DMSO and MSM (and/or acompound related to MSM) exhibit reduced odor than formulationscomprising DMSO alone. Formulations in liquid, gel, solid, and/orgaseous forms exhibit reduced odor when DMSO is combined with MSM(and/or a compound related to MSM) in some embodiments.

In several embodiments, the invention comprises an oral and topicalsystem for improving the symptoms of arthritis (e.g., osteoarthritis),including, but not limited to, pain, osteophytes, stiffness, gripstrength, limited range of motion, tissue enlargement in joints,inflammation (specific to a joint or localized to a general region ofthe body), swollen joints, joint deformity, and combinations thereof. Inone embodiment, the system comprises a first formulation comprising DMSOand MSM, wherein said first formulation is suitable for oraladministration. In some embodiments, the first formulation comprisesabout 300 mg to about 750 mg MSM and about 10 mg to about 50 mg DMSO. Insome embodiments, the first formulation comprises about 300 mg to about700 mg MSM and about 10 mg to about 50 mg DMSO. The second formulationcomprises DMSO and MSM, and is suitable for topical administration. Insome embodiments, the second formulation comprises between about 100 mgand about 1500 mg MSM and between about 500 mg and about 5000 mg DMSO,depending on the volume applied. The second formulation, in someembodiments, comprises about 900 mg to about 1200 mg MSM and about 3000mg to about 5000 mg DMSO. In some embodiments, the second formulationcomprises about 10% to about 15% MSM and about 40% to about 70% DMSO, orhigher (e.g., up to 90% or more DMSO).

In one embodiment, the first formulation (e.g., oral) comprises 650 mgMSM and 15 mg DMSO and the second formulation (e.g., topical) comprises10% MSM and 50% DMSO. In one embodiment, the first formulation comprises500 mg MSM and 15 mg DMSO and the second formulation comprises 917 mgMSM and 4585 mg DMSO. In one embodiment, an oral formulation comprises400-600 mg MSM and 10-20 mg DMSO and a topical formulation comprises800-1000 mg MSM and 3500-5000 mg DMSO.

In one embodiment, the first formulation comprises about 900 mg to about2100 mg MSM and about 30 mg to about 150 mg DMSO and the secondformulation comprises about 10% to about 15% MSM, and about 50% to about90% DMSO. In one embodiment, the first formulation comprises about 900mg to about 2100 mg MSM and about 30 mg to about 150 mg DMSO and thesecond formulation comprises about 2700 mg to about 3600 mg MSM, andabout 9000 mg to about 15,000 mg DMSO.

In one embodiment, the first formulation comprises about 1500 mg MSM andabout 45 mg DMSO and the second formulation comprises about 10% MSM andabout 50% DMSO. In one embodiment, the first formulation comprises about1500 mg MSM and about 45 mg DMSO and the second formulation comprisesabout 2751 mg MSM and about 10,800 mg DMSO.

In one embodiment, the first formulation comprises about 60-99% MSM, andabout 0.1-3% DMSO and the second formulation comprises about 10-15% MSM,and about 50-70% DMSO, or higher (e.g., up to 90% or more DMSO).

In one embodiment, the first formulation comprises about 60-70% MSM andabout 0.1-3% DMSO and the second formulation comprises about 10%-15% MSMand about 40%-90% (e.g., 50%-70%) DMSO.

In one embodiment, the first formulation comprises about 0.045g/day DMSOand about 1.85g/day MSM and the second formulation comprises about50%-70% DMSO and about 10%-15% MSM. In one embodiment, an oralformulation comprises about 0.045g/day DMSO and about 1.85g/day MSM anda topical formulation comprises about 40%-90% DMSO and about 10%-15%MSM.

In several embodiments herein, only the first formulation (e.g., oral)is used (alone or combined with other compounds). In other embodiments,only the second formulation (e.g., topical) is used (alone or combinedwith other compounds). In yet other embodiments, a dual treatmentapproach is employed. In some embodiments, the dual treatment approachcomprises an oral and topical therapy comprising DMSO, MSM and one ormore additional compounds.

In one embodiment, the therapeutic system is suitable for treating asubject, and is administered (or is suitable for administration) in thefollowing doses: the first formulation comprises about 10-30 mg MSM perkg body weight of the subject and about 0.1-1 mg DMSO per kg body weightand the second formulation comprises about 30-50 mg MSM per kg bodyweight and about 125-175 mg DMSO per kg body weight. In one embodiment,the second formulation comprises about 30-70 mg MSM per kg body weightand about 125-225 mg DMSO per kg body weight

In one embodiment, the first formulation and/or the second formulationare administered (or are suitable for administration) at least once,twice or thrice daily.

In several embodiments, the MSM reduces an odor or other side-effect ofthe DMSO. In some embodiments, MSM reduces dermal irritation that may becaused by administration of DMSO. In some embodiments, DMSO reduces aside-effect of the MSM. In some embodiments, DMSO enhances the efficacyof the MSM. In some embodiments, the enhanced efficacy of the MSM is dueto the DMSO in the oral formulation. In some embodiments, DMSO in theoral formulation reduces the amount of MSM that is required to achieve agiven therapeutic result. MSM used according to any of the embodimentsprovided herein may be isolated, purified or processed. MSM that hasbeen granted a GRAS (Generally Recognized As Safe) designation is usedfor several embodiments described herein.

In some embodiments, the first formulation is in a capsule, tablet, oralsuspension, liquid, inhalant, and/or effervescent form, wherein saidforms are optionally coated and/or flavored. The second formulation,according to some embodiments, is in a gel, cream, serum, liquid, spray,ointment, and/or patch form. Heat or cold therapy may be additionallyprovided in conjunction with the second formulation.

In several embodiments, the first oral formulation treats the chronicsymptoms of osteoarthritis and/or generalized pain and/or injury and thesecond topical formulation treats the acute symptoms of osteoarthritisand/or localized pain and/or injury. The first and/or the secondformulations are optionally provided in time-released formulations.

In one embodiment, the invention comprises the use of the formulationsdescribed herein in the preparation of a medicament for the treatment ofosteoarthritis and/or symptoms of osteoarthritis. In one embodiment, theinvention comprises a kit comprising one or more formulations accordingto any one of the preceding claims with instructions to administer thefirst formulation orally 1-4 times daily and/or instructions toadminister the second formulation topically 1-4 times daily. In oneembodiment, the instructions instruct the administration of the firstformulation orally 3 times daily. The instructions may also instructadministration of the second formulation topically 1-4 times daily forup to two weeks. In one embodiment, the instructions instruct theadministration of the second formulation topically 3 times daily for upto two weeks.

In several embodiments, the invention comprises a method for treatingthe symptoms of arthritis (e.g., osteoarthritis). Symptoms that aretreated in some embodiments include one or more of pain, osteophytes,stiffness, grip strength, limited range of motion, tissue enlargement injoints, swollen joints, and joint deformity. In some embodiments, theinvention comprises a method for treating the symptoms other types ofarthritis, such as, for example, adult onset rheumatoid arthritis. Insome embodiments, the invention is used to treat and/or improve thesymptoms of juvenile rheumatoid arthritis. In one embodiment, the methodcomprises providing the first and second formulation as disclosedherein, orally administering or instructing oral administration of thefirst formulation to a subject 1-4 times daily; and topicallyadministering or instructing topical administration of the secondformulation to said subject 1-4 times daily.

In several embodiments of the invention, a topical formulation forimproving the symptoms of osteoarthritis is provided. In one embodiment,the formulation comprises DMSO in an amount between about 2000 mg toabout 5000 mg DMSO per dose (e.g., a 5 mL dose) and MSM in an amountbetween about 300 mg to about 1200 mg MSM per dose (e.g., a 5 mL dose).In one embodiment, the formulation comprises DMSO in an amount betweenabout 3000 mg to about 5000 mg DMSO per dose and MSM in an amountbetween about 900 mg to about 1200 mg MSM per dose. In one embodiment,the DMSO and MSM are suitable for topical administration to a subject toimprove the symptoms of osteoarthritis. In one embodiment, the DMSO andMSM are suitable for topical administration to a subject to treat one ormore of joint disorders, inflammation, degeneration, and/or pain.Optionally, an oral formulation comprises about 300 mg to about 700 mgMSM and about 10 mg to about 50 mg DMSO per dose is provided.

In one embodiment, MSM is configured to act as a lubricant to reduceirritation associated with topical application of DMSO. In oneembodiment, MSM reduces the odor associated with topical application ofDMSO.

In one embodiment, the invention comprises a method of reducing theamount oral DMSO to achieve a therapeutic effect comprising: providingthe oral or topical formulation as described herein to reduce the amountof DMSO needed to achieve a therapeutic effect, thereby reducing theside effects of DMSO.

In several embodiments, the invention comprises an oral formulation forimproving the symptoms of arthritis (e.g., osteoarthritis). In oneembodiment, the formulation comprises DMSO and at least one secondcompound in a solid form that is encapsulated in a capsule or otherencapsulation format. In one embodiment, the capsule delivers said DMSOand at least one second compound in a time-released manner. In someembodiments, the oral formulation is analgesic and anti-inflammatory.The second compound reduces an odor associated with DMSO and reduces oneor more side effects associated with DMSO. In one embodiment, the secondcompound is MSM, urea, a sulfur-binding agent, or combinations thereof.In one embodiment, the second compound comprises a nutrient (e.g., anamino acid). In one embodiment, the second compound comprises a carbonylgroup attached to two organic amine residues. In one embodiment, thesecond compound includes carbamide peroxide, allantoin, and hydantoin,biurets, amides, carbamates, diimides, carbodiimides, thiocarbamides, orcombinations thereof. Preferably, one or more of MSM, urea and/or asulfur-binding compound are used, although other compounds are providedin several embodiments to reduce an odor or side-effect of DMSO.

In one embodiment, the encapsulated oral formulation is provided in adosage of about 1 gram or less. In one embodiment, the formulation issuitable for administration 1-4 times per day with or without food. Insome embodiments, the synergistic effects of DMSO and MSM do not requirethe formulation to be ingested with food. In several embodiments, theuse of MSM permits higher concentrations of DMSO to be used andtolerated, by for example, reducing the side-effects of DMSO and/orreducing the odor associated with DMSO. In one embodiment, the use ofMSM in amounts greater than 800 mg (e.g., in a single or daily dose)increase the tolerability of DMSO in amounts greater than 200 mg (e.g.,in a single or daily dose).

In several embodiments of the invention, a formulation comprising DMSOin a solid form is provided. In some embodiments, the DMSO is in a solidphase at room temperature. The DMSO in solid formulation is suitable forthe treatment of several disorders, including arthritis (e.g.,osteoarthritis, rheumatoid arthritis), and other disorders that wouldbenefit from DMSO treatment (e.g., osteophyte formation). In someembodiments, the solid formulation is used for the treatment ofinflammation, pain, or a combination thereof. In several embodiments,DMSO and MSM are combined to form a solid, wherein the solid remains asolid at room temperature. The solid formulation includes, but is notlimited to, a capsule, a gel-cap, a tablet, an oral suspension, apowder, an effervescent, or combinations thereof. A coating is providedin some embodiments. The coating provides sustained-release,sustained-action, extended-release, controlled-release, orcontinuous-release of the formulation according to several embodiments.In some embodiments, the coating further provides a flavorant. In oneembodiment, DMSO is between about 0.01% to about 10% by weight of theformulation. In another embodiment, DMSO is between about 45% to about55% by weight of the formulation. In one embodiment, the formulation isprovided in a capsule comprising about 100 mg to about 1000 mg of saidDMSO, wherein said capsule is suitable for delivery 1-4 times daily.

In several embodiments, the invention comprises a method for producingDMSO in a form that is solid at room temperature. In one embodiment, themethod comprises providing DMSO in a liquid form, combining said liquidDMSO with hydrogen peroxide, heating the liquid DMSO and the hydrogenperoxide to obtain a combination of DMSO and MSM, cooling the DMSO andMSM combination into a solid formulation, wherein said solid formulationis solid at room temperature. Flaking, prilling and/or freezing isperformed according to some embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts plasma concentrations of MSM after a 5 minute topicalexposure to 10% MSM and varied concentrations of DMSO.

FIG. 2 depicts the change from baseline of the MSM plasmaconcentrations.

DETAILED DESCRIPTION

The invention, in some embodiments, comprises a formulation comprisingDMSO and MSM, individually or combined, to treat the chronic effects ofosteoarthritis as well the acute symptoms associated withosteoarthritis. In several embodiments, the invention comprises atherapeutic system comprising DMSO and MSM, individually or combined, totreat generalized pervasive pain via an oral formulation and localizedpain via a topical formulation. In one embodiment, topical formulationsof DMSO and/or MSM are also effective for generalized pain. In severalembodiments, formulations comprising DMSO and MSM, individually orcombined, are multifunctional in that the formulations not only treatthe symptoms of an illness (such as osteoarthritis), but also conferunrelated benefits (e.g., improvements in skin and other aestheticbenefits, cardiovascular health, neurological health, immunity, vision,etc.).

As discussed herein, in several embodiments, there is provided an oraland topical dual formulation system for improving the symptoms ofarthritis (including but not limited to osteoarthritis), the systemcomprising a first formulation comprising DMSO and a sulfur-bindingand/or sulfur-based agent (including but not limited to MSM), whereinthe first formulation is suitable for oral administration, wherein thefirst formulation comprises about 300 mg to about 750 mg MSM (or otheragent) and about 10 mg to about 50 mg DMSO (e.g., about 650 mg MSM, orother agent, and about 15 mg DMSO) and a second formulation comprisingDMSO and MSM (or other agent), wherein the second formulation issuitable for topical administration, wherein the second formulationcomprises about 10% to about 15% MSM (or other agent) about 40% to about70% DMSO, or higher (e.g., about 10% MSM, or other agent, and about 50%DMSO).

Unless stated otherwise, percentages of MSM, DMSO or other compoundsprovided herein are provided as % by weight.

In one embodiment, a dual formulation system comprising an oral dosageof 500 mg MSM and 15 mg DMSO together with a topical dosage of 50% DMSOand 10% MSM is provided. The oral dosage may be in the form of a tablet,capsule, powder, liquid, oral suspension, effervescent, or any otherform suitable for oral delivery. The topical dosage may be in the formof a spray, gel, cream, lotion, patch, or any other form suitable fortopical delivery. In some embodiments, the formulation is administeredintravenously or via inhalation in addition to, or instead of, oraladministration.

In several embodiments, the combined use of MSM reduces or eliminatesthe odor normally associated with DMSO. In some embodiments, the use ofsolid DMSO reduces or eliminates the odor normally associated with DMSO.The odor reduction is surprising, and beneficial in several embodimentsbecause practitioners have avoided using DMSO in high concentrations (orin any amount) because of its unpleasant odor.

In some embodiments, the invention comprises an oral formulation of DMSOand MSM. In other embodiments, the invention comprises a topicalformulation of DMSO and MSM. According to one embodiment, the topicalformulation is particularly advantageous because MSM reduces oreliminates the skin irritation that can result from that topicalapplication of DMSO. For example, in some embodiments, MSM acts as alubricant and/or barrier that shields the skin from DMSO while stillpermitting penetration. In one embodiment, topical DMSO inconcentrations greater than 25% (e.g., 50%, 70%, or more) are toleratedbecause of the presence of MSM. In one embodiment, the presence of MSMreduces the formation of rash, redness, dryness of skin, itching, and/orcombinations thereof. In one embodiment, MSM reduces the occurrence,probability or symptoms associated with a generalized allergic reactionto DMSO, including heart arrhythmias and breathing difficulties. Becausehigher concentrations of DMSO can be administered topically in certainembodiments, the oral dose of DMSO can be reduced, thereby reducing thegastrointestinal side effects that can result from the topicaladministration of DMSO.

In several embodiments, the amount of DMSO is reduced when combined withMSM because of additive or synergistic effects between DMSO and MSM. Inseveral embodiments, the amount of MSM is reduced when combined withDMSO because of additive or synergistic effects between DMSO and MSM. Inseveral embodiments, MSM is provided in solution in a concentration ofless than about 15%. In some embodiments, oral doses of MSM of less thanabout 2 grams per day are administered (e.g., 1 g, 1.5 g, 1.75 g and1.85 g) to reduce gastrointestinal side effects in certain applications.In several embodiments, DMSO increases the penetration of MSM intotissue (e.g., skin).

In another embodiment, a formulation comprises, consists or consistsessentially of an oral dosage (e.g., a solid form) of about 200 mg toabout 2000 mg MSM and about 1 mg to about 100 mg DMSO together with atopical dosage of about 5% to about 90% DMSO and about 1% to about 50%MSM. In some such embodiments, MSM in the oral dosage ranges from about200 to 500 mg, 500 to 800 mg, 800 to 1100 mg, 1100 to 1400 mg, 1400 to1700 mg, 1700 to 2000 mg, and overlapping ranges thereof. In some suchembodiments, DMSO in the oral dosage ranges from about 10 to 30 mg, 30to 50 mg, 50 to 70 mg, 70 to 90 mg, 80 to 100 mg, and overlapping rangesthereof. In one embodiment, the invention comprises, consists orconsists essentially of about 200 mg to about 2000 mg MSM and about 1 mgto about 100 mg DMSO, e.g., 400-600 mg MSM and 10-20 mg DMSO, 500 mg MSMand 15 mg DMSO, or 650 mg MSM and 15 mg DMSO.

In several embodiments, the invention comprises an oral formulation(e.g., a solid form) comprising a ratio of MSM to DMSO of 33:1, andoptionally, a topical formulation comprising a ratio of MSM to DMSO of1:5. In other embodiments, the invention comprises an oral formulationhaving a ratio of MSM to DMSO of 30-50:1, and optionally, a topicalformulation having a ratio of MSM to DMSO of 1:2-10. In yet otherembodiments, the invention comprises an oral formulation having a ratioof MSM to DMSO of 25-35:1, and optionally, a topical formulation havinga ratio of MSM to DMSO of 1:3-7. The ratio of MSM to DMSO in severalembodiments is surprisingly advantageous because the MSM synergisticallyimproves the efficacy of DMSO. Thus, DMSO, which may have side effectswhen administered at certain concentrations, may be provided at lowerconcentrations to offer the same or better therapeutic efficacy. Asdiscussed herein, the presence of MSM in certain embodiments functionsas an emollient. In some embodiments, MSM reduces the odor normallyassociated with DMSO.

In some embodiments, the invention comprises a method of managing thesymptoms of osteoarthritis by administering an oral dosage of MSM andDMSO daily for at least 1 month, together with a topical dosage of DMSOand MSM daily for about two weeks. Certain embodiments are particularlyadvantageous because they permit fast-acting symptom relief with thetopical dosage, while allowing the oral dosage to gradually providelong-term relief. In some embodiments, relief is provided for extendedperiods of time, e.g., a week or more, several weeks, about a month, twomonths or more. At the point when the oral dosage becomes effective,patients can discontinue repetitive use of the topical formulation, thusreducing the risk of skin irritation and/or localized bioaccumulation.In still other embodiments, once the oral dosage has reduced pain and/orsymptoms, the topical formulation is not necessary. In some embodiments,the dosage of the oral or the topical formulations is adjusted topersonalize the therapy for a particular individual. For example, if anindividual normally has limited chronic symptoms, but severe acutesymptoms, a lower dose oral formulation with a higher dose topicalformulation may be used. In other embodiments, an individual with moresevere chronic symptoms, and few acute symptomatic episodes may benefitfrom a higher dose oral formulation and a less concentrated topicalformulation. Thus, a dual formulation comprising both oral and topicalroutes of administration are surprisingly advantageous in severalembodiments.

Oral formulations comprising MSM and DMSO, individually or combined, areadministered multiple times per day in certain embodiments. In someembodiments, dosing occurs two, three, four or more times daily,depending on the severity of the osteoarthritis symptoms. In otherembodiments, oral formulations are taken once per day. Topicalformulations, in certain embodiments, are used multiple times daily, forexample two, three, four or more times. In other embodiments, topicalformulations are used only for treatment of acute exacerbation ofsymptoms. In some embodiments, oral formulations are used in conjunctionwith topical formulations, while in other embodiments, only oralformulations are administered.

In certain embodiments, formulations comprising MSM and DMSO,individually or combined, (oral, topical, or combinations thereof) areefficacious in ameliorating one or more symptoms of osteoarthritis. Insome embodiments, formulations comprising MSM and DMSO, individually orcombined, reduce or prevent pain or stiffness in one or more jointsduring periods of rest. In some embodiments, formulations comprising MSMand DMSO, individually or combined, reduce or prevent pain or stiffnessin one or more joints during periods of light or moderate activity. Instill other embodiments, formulations comprising MSM and DMSO,individually or combined, reduce or prevent pain or stiffness in one ormore joints during periods of strenuous activity. In severalembodiments, formulations comprising MSM and DMSO, individually orcombined, reduce pain, stiffness and/or inflammation at rest, duringactivity, and/or post-activity.

In several embodiments, the combination of DMSO and MSM in a singleformulation results in a synergistic effect, thereby lowering theconcentration of DMSO, MSM, or both DMSO and MSM needed to effectivelyreduce one or more symptoms of osteoarthritis. Toxicology studies haveestablished that DMSO can be chronically administered at 5 g/kg dailywithout any serious adverse effects. In certain embodiments, the dosageof oral DMSO ranges from about 0.003 to 0.06 g per day. In someembodiments, the dosage of oral DMSO is about 0.045 g per day. Assumingan average of 50 kg per subject, these dosages equate to a range ofabout 0.00006 to about 0.0012 g/Kg daily (0.0012 to 0.024% of the dosegiven in the toxicology studies without serious adverse effect).

Oral toxicity of MSM has been previously determined through standardmethods in rats. The LD₅₀ value was approximately 17 g/kg, whichcorresponds to an oral dose of 2.6 pounds per day for a 150 pound human.In certain embodiments, the dosage of oral MSM ranges from about 1.0 to2.5 g per day. In some embodiments, the dosage of oral MSM is 1.95 g perday. In other embodiments, MSM is administered (e.g., orally) in adosage of up to about 6 g/day. These doses are well below the range oftoxicity determined for MSM. At this dosage level, MSM reducesinflammation and radiological changes in the joint in severalembodiments.

In certain embodiments, the synergistic effects between DMSO and MSMreduce the concentration of DMSO and/or MSM required to function as aneffective anti-inflammatory or to generate analgesic effects. In certainembodiments, the synergy reduces the concentration of DMSO and/or MSMrequired to prevent structural changes to affected joints, the articularcartilage of joints and the juxtaposed subchondral bone. In severalembodiments, DMSO functions to facilitate the activity of MSM (e.g.,analgesia, anti-inflammatory effects, and the like). In someembodiments, DMSO provides further positive effects on the same aspectsof a disease or condition that MSM positively impacts. Thus, in someembodiments, DMSO supplements and also facilitates the actions of MSM.

Further, the synergistic effects of certain embodiments reduce theamount of time from inception of treatment to amelioration ofosteoarthritis symptoms. In some embodiments, this time period isreduced several fold, for example from the order of several months downto the order of several weeks. In certain embodiments, the synergisticeffects result in symptomatic improvement within about 2 to 6 weeks.

In several embodiments, a formulation comprising DMSO and MSM lowers theamount of MSM required orally. In one embodiment, DMSO allows MSM topenetrate skin more effectively. According to some embodiments, thecombination permits lower amounts of both DMSO and MSM to be usedtherapeutically, and optionally lowers odor, gastrointestinal symptoms,and/or the size of the capsule (or pill, tablet, or other dosageformat). In one embodiment, MSM binds with DMSO metabolites for furtherodor reduction. In some embodiments (e.g., liquid forms for children), aflavor is added to DMSO and MSM to improve taste. Formulationscomprising DMSO and/or MSM may also be added to therapeuticconfectionaries, such as chews and gummies.

The synergism of DMSO and MSM according to several embodiments, allowsreductions in the concentrations needed to effectively reduceosteoarthritis symptoms. In certain embodiments, the MSM functions as askin protectant and unexpectedly protects the skin from the adverseeffects of DMSO exposure. In some embodiments, topical MSM functionsprimarily as an inactive ingredient, e.g., it functions primarily tominimize dermal irritation that may otherwise be induced by topical DMSOadministration. In some embodiments, MSM functions as a lubricant forthe skin (e.g., to prevent excessive drying of the skin). In certainembodiments, the efficacious concentration of DMSO for lower limb jointtreatment is reduced to 50% DMSO, or lower. In certain embodiments, theefficacious concentration of DMSO for upper limb joint treatment isreduced to 25-50% DMSO. In some embodiments, the duration that the skinis exposed to DMSO is reduced, because the DMSO/MSM formulation is moreefficacious than DMSO alone. Thus, in certain embodiments, the DMSO/MSMtopical formulation is left on the skin for 2-15 minutes and thenremoved (e.g., washed off). In other embodiments, DMSO/MSM topicalformulation is left on the skin for about 5-10 minutes and then removed(e.g., washed off). In such embodiments, the possibility of side effectsfrom DMSO exposure is reduced due to the reduction in exposure time andthe protectant effects of MSM. However, in further embodiments, DMSO/MSMtopical formulation is left on the skin and not removed. In someembodiments, DMSO and/or MSM act as antioxidants.

In several embodiments, the penetrant effect of DMSO allows MSM toachieve greater skin penetration and absorption, allowing enhancedanti-inflammatory effects. In some embodiments, the DMSO/MSM topicalformulation unexpectedly provides analgesic effects. Further, thesynergism exhibited by DMSO and MSM in the topical formulations canimprove osteoarthritis symptoms in as little as about ½ a day to about 3days, according to several embodiments. In some embodiments, DMSO and/orMSM are analgesic when provided in an oral dosage form.

In some embodiments, the synergism of DMSO and MSM, and the associatedreduction in doses of both compounds, enables the simultaneous use ofboth oral and topical formulations. The reduced concentrations of DMSOand MSM (as compared to therapies of either DMSO or MSM alone),according to several embodiments described herein, reduce the overalloccurrence of side effects and thereby enable simultaneous use of oraland topical formulations. Such embodiments therefore allow use of atopical formulation to ameliorate any acute joint pain, while the oralformulation serves to lower inflammation and pain on a chronic basiswith minimal complications.

In some embodiments, the combination of DMSO and MSM and/or the use ofsolidified DMSO unexpectedly reduces the unpleasant odor normallyexperienced with DMSO use. For example, in certain embodiments,formulations comprising DMSO and MSM produce no perceptible odor afteruse. In some embodiments, a formulation comprising 10%-50% MSM reducesor eliminates the odor of DMSO provided at a concentration of 50%-90%.Previously, DMSO used at concentrations approaching 50% (or more) wereassociated with a strong unpleasant odor that could be detected throughthe skin or on the breath of a patient. Thus, several embodiments of thecompositions described herein are unexpectedly advantageous because theyreduce or eliminate the odor-related side effect.

According to any of the embodiments disclosed herein, a therapeuticsystem comprising MSM and DMSO, individually or combined, also includesone or more of the following compounds: ibuprofen, fenoprofen,indomethacin, naproxen, tolmetin, salicylic acid, and sulindac. In otherembodiments, a therapeutic system comprising DMSO and/or MSM alsoincludes one or more of the following compounds: antioxidants,glucosamine, chondroitin, niacinamide, S-adenosylmethionine, curcumin,quercetin, omega-3 fatty acids, papain, hyaluronic acid, and bromelain.In several embodiments, a formulation comprising DMSO and/or MSM andabout 500-2500 mg glucosamine is provided. One or more of the followingcompounds may be used in addition to, or in place of, glucosamine: about500-5000 mg fish oil, about 500-5000 IU Vitamin D, about 500-2500 mgchondroitin, 500-5000 mg or IU antioxidants (such as vitamin C, E orbeta-carotene), about 500-2500 mg curcumin, and about 50-2500 mghyaluronic acid. In some embodiments, formulations comprising DMSOand/or MSM inhibit the secretion of pro-inflammatory enzymes that arecontribute to the breakdown of cartilage, including collagenase,hyaluronidase, and elastase. In some embodiments, formulationsconsisting or consisting essentially of DMSO and/or MSM inhibit thesecretion of pro-inflammatory enzymes that are contribute to thebreakdown of cartilage.

In several embodiments, a formulation comprising DMSO and/or MSM withouta gastroprotectant is provided. Thus, several embodiments of theinvention are particularly advantageous because it is estimated thatmany severe arthritic patients who are receiving NSAIDs are alsoco-prescribed a gastroprotectant.

In certain embodiments, the amount of DMSO in a topical formulationranges from about 0.01% by weight to about 70% by weight. In otherembodiments, the formulation comprises between about 0.01% and 10% DMSOby weight, and overlapping ranges thereof. Other embodiments comprisebetween about 10% and 20% DMSO, about 20-30% DMSO, about 30-40% DMSO,about 40-50% DMSO, about 50-60%, or about 60-70% DMSO, and overlappingranges thereof. Still other embodiments comprise a formulationcomprising between about 7% and 15% DMSO, about 15-25% DMSO, about25-35% DMSO, about 35-45% DMSO, about 45-55% DMSO, about 55-60%, about60-65%, or about 65-70%, and overlapping ranges thereof. In certainembodiments, DMSO is present in a range between about 45-55% by weight,including 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, and 55%, andoverlapping ranges thereof. In some embodiments, DMSO is provided in arange from about 70% to about 90%. Higher concentrations of DMSO mayalso be used in other embodiments.

In certain embodiments, the amount of MSM in a topical formulationranges from about 0.01% by weight to about 70% by weight. In someembodiments, the formulation comprises between about 0.01% and 10% MSMby weight, and overlapping ranges thereof. Other embodiments comprise aformulation comprising between about 10% and 20% MSM, about 20-30% MSM,about 30-40% MSM, about 40-50% MSM, about 50-60%, or about 60-70% MSM,and overlapping ranges thereof. Still other embodiments comprise betweenabout 7% and 15% MSM, about 15-25% MSM, about 25-35% MSM, about 35-45%MSM, or about 45-55% MSM, and overlapping ranges thereof. In certainother embodiments, MSM is present in a range between about 5-15% byweight, including 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15%, andoverlapping ranges thereof. In some embodiments, MSM is provided in arange from about 70% to about 90%. Higher concentrations of MSM may alsobe used in other embodiments. In several embodiments, the percentagesabove are based on the volume of MSM used in an embodiment.

In several embodiments, a topical formulation MSM and DMSO, individuallyor combined, is provided in a concentration sufficient for applicationto the body in a thin layer. In one embodiment, the DMSO/MSM formulationis wiped across the surface of a joint in a thin layer and removed aboutfive to ten minutes later with, for example, a wet wash cloth. In oneembodiment, the target tissue (e.g., skin of the knee or other joint) iscleaned to deter the penetration of contaminants by DMSO. In someembodiments, volumes of the topical formulation applied range from about0.5 mL to about 10mL, depending on the tissue to which the formulationis applied. Thus, in some embodiments, the amount of the topicalformulation applied in one use is between about 0.5mL to about 1 mL,about 1 mL to about 3 mL, about 3 mL to about 5 mL, about 5 mL to about7 mL, about 7 mL to about 10 mL, about 10 mL to about 20 mL, andoverlapping ranges thereof In some embodiments, a formulation comprisingMSM, DMSO, or a combination of MSM and DMSO is provided in a topicalformulation and a user is instructed to apply about 3 mL to about 15 mLper application per body part (e.g., knee).

In several embodiments, the topical formulation comprising MSM and DMSO,individually or combined, further comprises one or more inactiveingredients including, among others, de-ionized water and variouspolymers (for example, carbopol 974 NF). Active ingredients may also beprovided. In some embodiments, a formulation consisting or consistingessentially of MSM and DMSO, individually or combined, is provided.

In some embodiments, formulations comprising DMSO and urea, andoptionally MSM are provided to reduce odor. In some embodiments,formulations comprising DMSO and sulfur-binding compounds are used toreduce odor. In some embodiments, formulations comprising DMSO and atleast one odor-reducing nutrient are used to reduce odor. In severalembodiments in which odor is reduced, odors associated with theoxidation, metabolism, degradation or other conversion of DMSO arereduced. For example, in one embodiment, odors associated withmethylthiomethane (DMS) are reduced. In some embodiments, MSM is used toreduce the odor of DMS that is produced by bacterial transformation ofDMSO waste that is disposed (e.g., into sewage systems).

In several embodiments in which odor is reduced, odors associated withthe oxidation, metabolism, degradation or other conversion of DMSO arereduced. In some embodiments, odors are reduced through the binding ofodiferous compounds. In some embodiments, odors are reduced by reducingthe production of odor-causing compounds. In some embodiments, odors arereduced by increasing the degradation of odor-causing compounds.According to one embodiment, compounds such as MSM are provided toreduce the odor associated with DMSO use by reducing the formation ofDMSO metabolites or by binding to DMSO metabolites (e.g., DMS).

In several embodiments, a combined topical and oral DMSO/MSM formulationis used to treat osteoarthritis of the knee. In some embodiments, theformulation is used to treat a condition in which the patient has bothknee pain and osteophytes (bone spurs) visualized on radiographs or whenthe patient is 40 years of age (or older), has morning knee stiffnesslasting 30 minutes or less, and crepitus (grating, crackling or poppingsounds) is detectable on motion of the knee.

In several embodiments, a combined topical and oral DMSO/MSM formulationis used to treat osteoarthritis of the hand. In some embodiments, theformulation is used to treat a condition in which a patient has handpain, aching or stiffness, hard tissue enlargement of two or more of 10selected joints, fewer than three swollen metacarpophalangeal joints,and hard tissue enlargement of two or more distal interphalangealjoints. In other embodiments, the formulation is used to treat acondition in which a patient has deformity of two or more of 10 selectedjoints (second and third distal interphalangeal joints, the second andthird proximal interphalangeal joints and the first carpometacarpaljoints (of both hands).

In several embodiments, a formulation comprising DMSO and MSM, alone orcombined, is used to treat one or more joints of a patient, includingbut not limited to the knee, toe, thumb, finger, ankle, spine, hip,shoulder or other joint. In some embodiments, a formulation comprisingDMSO and MSM, alone or combined, is used to treat lower back pain (e.g.,pain in or associated with spinal column).

According to any of the embodiments disclosed herein, a combined topicaland oral formulation comprising MSM and DMSO, individually or combined,is used to treat cartilage degeneration and/or degeneration ofsubchondral bone. In some embodiments, the formulation prevents, haltsor treats bone spur formations, calcified areas and/or other undesiredformations. A combined topical and oral DMSO/MSM formulation may also beused to treat joint pain, tenderness, stiffness, creaking, locking ofjoints, and/or local inflammation. In several embodiments, a combinedtopical and oral DMSO/MSM formulation is used to positively affect oneor more of the following measures: (i) Radiological testing for both theknee and hand; (ii) Likert pain index on resting for both the knee andhand; (iii) Fuchs swelling index for both the knee and hand; (iv) Rangeof motion for both the knee and hand (or other joint); (v) Visual analogscale -pain intensity (VAS-PI) with loading for both the knee and handand VAS Patient global assessment; (vi) The Lequesne index for the knee;(vii) WOMAC (Western Ontario and McMaster Osteoarthritis) physicalstiffness and pain scale for the knee; (viii) Functional Index for HandOsteoarthritis; (ix) Grip strength measurement; and (x) Rescuemedication usage. Improvements of about 5%-100% in the identifiedmeasures are provided according to several embodiments (e.g.,improvements of about 10-25%, 25-50%, 50-75%, 75-100%, and overlappingranges thereof). Improvements in pain and inflammation may also beaccompanied by increased range of motion, grip strength and generalability to perform daily activities according to several embodiments.

In several embodiments, a formulation comprising MSM and DMSO,individually or combined, is used to treat weakness, inflammation and/orpain in the hand, knee, or other joint. The formulation can beadministered orally, topically, orally, or both orally and topically.

According to any of the embodiments disclosed herein, an oralformulation comprising MSM and DMSO, individually or combined, is usedexclusively (without the topical treatment). According to any of theembodiments disclosed herein, a formulation comprising MSM and DMSO,individually or combined, is provided in a form suitable foradministration intravenously, intra-articularly, and/or via inhalationin addition to or instead of oral administration. In some embodiments,the formulation is administration intravenously, intra-articularly,and/or via inhalation in addition to or instead of topicaladministration.

In several embodiments, subjects treated with a formulation comprisingMSM and DMSO, individually or combined, include humans, non-humanmammals, domesticated animals and livestock. In some embodiments, aformulation comprising MSM and DMSO, individually or combined, is usedto not only treat undesired symptoms and illnesses, but can also act asa preventative. For example, an oral and/or topical formulationcomprising MSM and DMSO, individually or combined, may be taken on aregular basis to prevent the onset of illness. Reversal ofosteoarthritis is provided in several embodiments, while in otherembodiments, formulations comprising MSM and DMSO, individually orcombined, prevent the onset or progression of the disease.

Formulations Comprising Solid DMSO

In several embodiments, a formulation comprising solid DMSO, alone or incombination with MSM, is provided. Pure DMSO is typically a clear andcolorless dipolar liquid at room temperature with a melting point of18.4° C. (or 65° F.), a flash point of 95° C., and a boiling point of189° C. at sea level. It is an aprotic and very hygroscopic chemicalwith a molecular weight of 78.13. However, application or ingestion ofDMSO often yields an unpleasant odor, which “tastes” like garlic shortlyafter it contacts the skin. In addition, irritation, dryness, rednessand/or itching of the skin can develop where DMSO is applied topicallyin repeated doses or in high concentrations. Other side effects of DMSOcan include sensitivity to light, visual disturbances, headache, nausea,upset stomach, and diarrhea. Side effects, such as allergic reactions toDMSO, can occur in certain cases, e.g., palpitations, arrhythmias,and/or respiratory issues. Undesired effects of DMSO may be caused byDMSO, its metabolism, catalysis, oxidation, degradation, and/or otherconversion. Due to its physical properties, DMSO is typically utilizedin its liquid form.

MSM is an organosulfur compound that is a metabolite of DMSO and certainsulfur-containing amino acids. It is a white, water-soluble powder witha melting point of 109° C., a flash point of 143° C., and a boilingpoint of 248° C. It has a molecular weight of 94.13.

Due to its physical properties, DMSO exists as a liquid at roomtemperature, and is therefore typically utilized as a liquid. However,there is a long felt and as yet unmet need for a solid form of DMSO atroom temperature. For example, solid forms of DMSO are particularlyadvantageous because they (i) are able to be manufactured or packagedinto pill, tablet or capsule form; (ii) are able to achieve concentratedforms (about 2-50 fold more concentrated than liquid forms per dosesize); (iii) exhibit reduced side effects as compared to the liquid form(e.g., less irritation, sensitivities, gastrointestinal effects, etc.);and (iv) exhibit reduced or no odor as compared to the liquid form. Insome embodiments, the use of DMSO that stays solid at room temperatureis particularly advantageous because it permits the inclusion of DMSOinto capsules (or other packaging) that would normally be degraded byliquid DMSO.

In some embodiments, DMSO that is solid at room temperature is provided.In some embodiments, DMSO that is solid at temperatures between 70-80°F., 80-90° F., 90-100° F., 100-125° F., and higher than 125° F. isprovided. In other embodiments, DMSO that is solid at room temperatureis provided, wherein said DMSO liquefies at about 65° F.

In accordance with certain embodiments, surprisingly, the combination ofDMSO and MSM yields a solid form of DMSO at room temperature. In someembodiments, DMSO and MSM are combined by mixing hydrogen peroxide witha liquid form of DMSO. In these embodiments, the hydrogen peroxide andDMSO are heated. In some embodiments, MSM is formed, but not all of theDMSO is removed. In certain other embodiments, DMSO and MSM are combinedby mixing a liquid form of DMSO in a MSM solution. In these embodiments,the solution can be heated and agitated. In some embodiments, DMSO andMSM are combined by mixing a solid form of MSM in a liquid form of DMSO.In other embodiments, DMSO and MSM are combined by mixing a liquid formof DMSO with a molten form of MSM.

In one embodiment, liquid DMSO is used as a starting material. Theliquid form of DMSO is mixed with hydrogen peroxide (H₂O₂) at atemperature and time sufficient for substantially all of the hydrogenperoxide to be consumed and for MSM and water by-product to form. Incertain embodiments, not all of the DMSO is removed, thereby yielding amolten DMSO/MSM combination that may subsequently be cooled. Forexample, in one embodiment, liquid DMSO at a concentration of about90-100% is combined with 30% to 51% H202 at stoichiometric ratio and atemperature of about 230-250° F. until at least 90% of the H202 isconsumed, and a product containing about 0.1%-15% DMSO and 85%-99.9% MSMis produced. Extreme caution must be maintained as this is an extremelyexothermic reaction.

In several embodiments, the preparation of MSM involves a hightemperature distillation step which results in molten MSM. In suchembodiments, DMSO may be added back into the molten MSM in knownquantities under agitation. In some embodiments, the DMSO added back isin liquid form, while in other embodiments, the DMSO is in solid form.The resultant DMSO/MSM combination is further agitated and then rapidlycooled in one embodiment.

In one embodiment, the molten DMSO/MSM combination is sent to a spraycooler/prilling chamber to form solid prills or microprills(microspherical pellets). In certain embodiments, the molten DMSO/MSMcombination is fed into the prilling chamber where the molten DMSO/MSMcombination enters a droplet generator to discharge the material in theform of droplets. As the droplets fall freely, they are cooled andsolidify into spheres or prills. The spheres or prills have a diameterin the range of about 75 microns to 840 microns (e.g., about 75-150microns, about 150-300 microns, about 300-450 microns, about 450-600microns, about 600-840 microns, and overlapping ranges therein).

In certain embodiments, the droplets are cooled with a flow of cold gas,such as but not limited to air, nitrogen gas, or carbon dioxide. Incertain other embodiments, the droplets are cooled with a spray of coldwater or cold liquid nitrogen. In other embodiments, the droplets arecooled by dry ice. In accordance with certain embodiments describedherein, after the droplets are cooled, since the exteriors of thedroplets cool first, the prills can remain in the cool temperature tosolidify the interiors of the prills.

In certain other embodiments, the molten DMSO/MSM combination (e.g.,mixture) is sent to a flaking system to form solid flakes. For example,in one embodiment, the molten DMSO/MSM combination is sent to a drumflaker, where a thin warm layer of the molten DMSO/MSM combination isapplied to the outside of a rotating drum. As the drum rotates, acooling agent housed within the rotating drum cools and solidifies thelayer of material on the exterior of the drum, and a knife scraperremoves the material in the shape of flakes. Various cooling agents canbe used, for example, liquid nitrogen, liquid oxygen, cooled water, orcooled water containing polypropylene glycol.

In accordance with several embodiments described herein, MSM can bepurified prior to combining it with DMSO. In some embodiments,purification is accomplished by distillation, among other methods. Incertain embodiments, DMSO powders or flakes are combined with MSM prill.In other embodiments, DMSO powders or flakes are combined with MSMflakes. In other embodiments, DMSO powders or flakes are combined withMSM powder. In certain embodiments, a homogenous mixture of DMSO/MSM isproduced, while in other embodiments, a non-homogenous mixture results.

In accordance with several embodiments described herein, MSM may becombined with DMSO to form a DMSO/MSM solution, and the resultant mixedsolution is subsequently frozen and ground into powder. In someembodiments, the liquid phase of the DMSO/MSM solution is water. In someembodiments, distilled, deionized, or distilled-deionized water is used.In other embodiments, other liquids may used. For example, the DMSO/MSMsolution may contain normal saline, or another acceptable solvent. Incertain embodiments, the ionic characteristics of the liquid may beadjusted to affect the resultant DMSO/MSM product. In some embodiments,other ingredients are added into the solution, with the solution heatedand agitated to facilitate mixing. The DMSO/MSM solution can be cooledand frozen. For example, the liquid DMSO can be cooled in a coolingchamber containing cold gas, such as but not limited to air, nitrogengas, or carbon dioxide. The DMSO/MSM combination is then ground by anygrinding or milling technique well known in the art or yet to bedevised.

In other embodiments, DMSO is added to molten MSM. In certainembodiments, the DMSO/MSM combination is formed into a solid by a spraycooler/prilling chamber as described above. In other embodiments, theDMSO/MSM combination is formed into a solid by a flaking system asdescribed herein.

In some embodiments, the purity of the starting raw materials can bealtered to adjust the purity of the end product. Depending on the levelof purity required, one or more purification processes may be employed.For example, in some embodiments where DMSO is the starting material,impurities can exist because DMSO is a strong solvent. Thus, thestarting MSM and/or DMSO may be purified prior to the manufacture of theDMSO/MSM combination. In some embodiments, the synthesis of MSM fromDMSO yields side reactions and compounds. In some embodiments,additional purification can be performed after the DMSO/MSM product isformed.

In one embodiment, distillation is employed as the purification process.Other contaminant/by-product removing procedures may be used instead of,or in addition to, distillation. Distillation removes the water andcontaminates from the raw materials and from side reactions. Inaccordance with some embodiments described herein, distillation can forma molten MSM into which DMSO may be added. In some embodiments, theDMSO/MSM combination is tested after production to reduce potentialhazardous heavy metals, such as lead, mercury, cadmium, and arsenic, tolevels below specified standards.

In some embodiments, gelatin and/or hydroxypropyl methylcellulose (HPMC)is used with the organic based solvent system to form a gel-cap. Inother embodiments, the organic based solvent system is used to form atablet. In some embodiments, the tablet is uncoated. In someembodiments, the tablet is coated. In certain embodiments, the coatingis pH stable and provides a time-release effect, such that the tablet ispositioned in a portion of the gastrointestinal tract that is highlyabsorptive, such as the ileum.

In several embodiments, the organic based solvent system is used toformulate an orally consumable effervescent DMSO/MSM formulation,allowing for enhanced absorption of DMSO and MSM. For example, incertain embodiments, a DMSO/MSM powder is produced that when added to aconsumable liquid, dissolves and yields and effervescent beverage forconsumption. In certain embodiments, the DMSO/MSM powder is pre-packagedinto single-dose serving sizes. In other embodiments, formulationscomprising DMSO and MSM, alone or combined, are formulated into a tabletthat can similarly be dissolved to produce an effervescent beverage. Anyconsumable liquid may be used to dissolve, the powder or tablet, withthe taste of the liquid being driven by the choice of the consumer. Inother embodiments, flavors may be added to the DMSO and/or MSM powder ortablet, such that, when combined with water, a flavored effervescentbeverage results.

In accordance with some embodiments described herein, a DMSO/MSM activecapsule is produced. In one non-limiting example, prior to or during theprocess to form the DMSO/MSM combination into a solid, vegetablecoating, amorphous silicon dioxide, and magnesium stearate are blendedand added into the DMSO/MSM combination to produce a formulationcomprising 650 mg of MSM, 15 mg of DMSO, 285 mg of Dritex-S Flakecoating, 4.75 mg of silicon dioxide, and 4.75 mg of magnesium stearate.The vegetable coating may be fully hydrogenated soybean oil that hasbeen further processed into flake form such as Dritex-S flakes and usedas an encapsulating agent. A placebo capsule can also be produced with aformulation consisting of 1 mg of DMSO, 950 mg of Pac-Gel 70, 4.75 mg ofsilicon dioxide, and 4.75 mg of magnesium stearate. In severalembodiments, as discussed herein, greater or lesser percentages of MSMand/or DMSO are used for active oral formulations. Placebos are alsoadjusted accordingly. In some embodiments, multilayer emulsions areprovided as coating materials. In one embodiment, nano-laminated lipidsare used as coating materials. Polymers are used in some embodiments. Insome embodiments, coatings comprise hydrogels, gelatins, soybean oil,malitol, or combination thereof

In accordance with certain embodiments described herein, topicalformulations, e.g., gels, lotions, and creams, can be produced by mixingDMSO into a MSM solution. In some embodiments, distilled, deionized, ordistilled-deionized water is used. In other embodiments, other liquidsmay used. For example, the MSM solution may contain normal saline, oranother acceptable solvent. In certain embodiments, other ingredientssuch as thickening agents, emulsifiers, and fragrances, used in topicalformulations which are well known in the art or yet to be devised can bemixed into the solution. In certain embodiments, the solution is heatedand agitated to facilitate dissolution. Once mixed, the solution isallowed to cool to form a gel, lotion or cream in some embodiments.

In one embodiment, an active topical gel is produced. In onenon-limiting example, 50 ml of de-ionized water is warmed on a hotplate. MSM (12 g) is added to the warm water and dissolved. Aftercomplete dissolution of the MSM, DMSO (60 g) is added to the MSMsolution. Crosslinked acrylic acid polymer (Carbopol 974 NF) is added tothe solution with constant agitation, which serves to wet the polymer asit is being added. The temperature of the solution is brought to betweenabout 50-60° C. and agitation is continued until the polymer iscompletely dissolved. Sodium carbonate (Na₂CO₃, 0.02 g) is dissolved inan additional 10 mL of deionized water. Once the Na₂CO₃ is completelydissolved, it is added to the DMSO/MSM/polymer solution withsimultaneous stirring by hand. Once thoroughly mixed, the solution isallowed to cool, resulting in a viscous gel of containing 50% DMSO/10%MSM with 1% Carbopol 974 NF and 39% de-ionized water. Viscosity ismeasured at approximately 300,000 cPs at 23° C. (73° F.). In severalembodiments, as discussed herein, greater or lesser percentages of MSMand/or DMSO are used for topical formulations. In several embodiments,percentages of DMSO and/or MSM are by volume, as stated, rather than byweight.

In certain embodiments described herein, formulations comprising DMSOand MSM, alone or in combination, are provided the form of a capsule, agel-cap, a tablet, oral suspension, a powder, or an effervescent. Gels,slurries, particles, powders and other dehydrated forms are alsoprovided in some embodiments. In certain embodiments, a formulationcomprising DMSO and MSM that is not liquid (e.g., a solid) at roomtemperature is provided. In some embodiments, solid formulations areadvantageous in that they maintain their consistency, e.g., maintain oneor more of a hardness, firmness, density, texture, and/or viscosity thatis at least 75%, 85%, 95% or 100% the same, over a wide range oftemperatures (e.g., from about 0° C. to about 100° C., about 5° C. toabout 50° C., about 10° C. to about 40° C., about 20° C. and about 30°C., and overlapping ranges thereof). Certain embodiments are coveredwith a coating while other embodiments are not coated. Where a coatingis provided, the coating may render a time-release effect. In certainembodiments, DMSO is between about 0.01% to about 10% by weight of theformulation. In several embodiments, the percentages above are based onthe volume of DMSO used in an embodiment.

In several embodiments, a solid formulation comprising DMSO is used inseveral industrial and medical applications. In some embodiments, solidDMSO is used for storing and transporting DMSO.

In several embodiments, the amount of DMSO in a solid formulationcomprising DMSO and MSM (and optionally other ingredients) ranges fromabout 0.01% by weight to about 90% by weight. In other embodiments, theformulation comprises between about 0.01% and 10% DMSO by weight. Incertain embodiments DMSO is present in about 0.01% to about 5%, about0.01% to about 2.5%, or 0.01% to about 2.0%. In some embodiments, DMSOis present in about 0.5% to about 1.75%, including 0.6, 0.7, 0.8, 0.9,1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.55, 1.6, 1.65, 1.7, and 1.75%, andoverlapping ranges thereof. Other embodiments comprise a formulationcomprising between about 10 and 20% DMSO, about 20-30% DMSO, about30-40% DMSO, about 40-50% DMSO, about 50-60% DMSO, about 60-70% DMSO,about 70-80% DMSO, about 80-90% DMSO. Still other embodiments comprisefrom about 7 to about 15% DMSO, about 15-25% DMSO, about 25-35% DMSO,about 35-45% DMSO, about 45-55% DMSO, about 55-65% DMSO, about 65-75%DMSO, or about 75-85% DMSO, and overlapping ranges thereof. Severalembodiments for capsules, gel-caps, powders, and effervescents comprisebetween about 0.01-10% DMSO, including 0.5, 1, 2, 3, 4, 5, 6, 7, 8, and9% DMSO. Several embodiments for gels, lotions, and creams comprise DMSOat a concentration of between 30% and 90%, for example, about 45-55%.

In several embodiments, the amount of MSM in a solid formulationcomprising DMSO and MSM (and optionally other ingredients) ranges fromabout 0.01% by weight to about 70% by weight. In other embodiments, theformulation comprises between about 0.01% and 10% MSM by weight. Otherembodiments comprise between about 10 and 20% MSM, about 20-30% MSM,about 30-40% MSM, about 40-50% MSM, about 50-60% MSM, or about 60-70%MSM including 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70% MSM, andoverlapping ranges thereof. Still other embodiments comprise aformulation comprising about 7 and 15% MSM, about 15-25% MSM, about25-35% MSM, about 35-45% MSM, about 55-60% MSM, about 60-65% MSM, orabout 65-70% MSM, and overlapping ranges thereof. Some embodiments forcapsules, gel-caps, powders, and effervescents comprise between about90-99% MSM, including 91, 92, 93, 94, 95, 96, 97, and 98% MSM. Severalembodiments for gels, lotions, and creams comprise between about 5 to15% MSM.

In some embodiments, the solid formulation is uncoated. In otherembodiments, the solid formulation is covered with a coating. In someembodiments, the coating provides a time-release effect (e.g.,sustained-release, sustained-action, extended-release,controlled-release, or continuous-release). Coatings, in someembodiments, incorporate a flavor additive, such that there is no chalkyor medicinal-tasting residue remaining after consuming the solidformulation. As used herein, “solid” shall be given its ordinary meaningand shall additionally refer to semi-solids, gels, viscous solutions,and other compounds that are not in liquid or gaseous phases. SolidifiedDMSO, alone or in combination with MSM, may be provided in the form oforal capsules, gel-caps, tablets, powders, and effervescents, or topicalgels, lotions, and creams. Other forms may also be manufactured. As usedherein, “compound” shall be given its ordinary meaning and shallinclude, but not be limited to, molecules, ingredients, atoms,substances and elements.

In some embodiments, one or more additional agents are added into theDMSO/MSM combination. In certain embodiments, pharmaceuticals, includingbut not limited to analgesics and anti-inflammatory agents, are employedwith the DMSO/MSM combination. In certain embodiments, antimicrobials,such as penicillin and antibiotics, can be employed with the DMSO/MSMcombination. In certain embodiments, vitamins and supplements are added.

In several embodiments, a solid formulation comprising MSM and DMSO,individually or combined, is provided that optionally comprises one ormore inactive ingredients including, among others, microencapsulatingagents (for example Dritex-S Flake coating), silicon dioxide, andmagnesium stearate. In several embodiments, a solid formulationcomprising MSM and DMSO, alone or in combination, is encapsulated to,for example, facilitate delivery, bioactivity, absorption, time-release,and/or palatability. In several embodiments, non-encapsulated powdersfacilitate delivery, bioactivity, absorption, time-release, and/orpalatability.

EXAMPLE

The following example is provided to further illustrate certainembodiments within the scope of the invention. The example is not to beconstrued as a limitation of any embodiments, since numerousmodifications and variations are possible without departing from thespirit and scope of the invention.

Example 1 Absorption of MSM in Topical Formulation is Within RecognizedSafe Levels

Approximately 17% of DMSO is metabolized into MSM in the body. DMSO hasbeen established to function as a penetration enhancer (among otherfunctions). This study investigated the circulating concentrations ofMSM when MSM is topically applied in combination with one of twoconcentrations of DMSO. According to the study, in some embodiments, MSMis not a pharmacologically active ingredient when applied topically.Rather, in some embodiments, topical MSM works synergistically with DMSOto reduce one or more side effects of DMSO. Thus, higher concentrationsof DMSO (which would otherwise be prohibitive because of the undesiredside effects) are able to be used to treat subjects.

New Zealand White rabbits, which are an accepted animal model for dermalabsorption studies, were used to assess the absorption and resultantblood levels of MSM. Rabbits were obtained from Charles River Canada(Saint-Constant, Quebec). Five male rabbits, ages 12-13 weeks (andranging in weight from 2.6 kg to 2.7 kg) were used for the dermalabsorption studies. Rabbits were used because of their greater skinpermeability as compared to rats, pigs or humans. Thus, testing onrabbits is a more conservative approach for the safety of topicalproducts for human use. The size of rabbit was based on the ethicalrestriction of collecting greater than 6 mL/kg body weight of bloodwithin a two week period. The total volume of blood to be removed duringthis study was 10 mL on a single day. One animal per group was used tominimize the number of animals required. Animals were housedindividually in stainless steel cages with 12 hours light/dark cycles.The animal room environment was monitored daily (targeted ranges: 18-26°C. and relative humidity 25-50%). Fresh air was supplied to the room ata sufficient rate to provide approximately 15 to 17 changes of room airper hour. Clinical observations were conducted for all animals to ensureanimals were in good health prior to dosing. Morbidity and mortalityobservations were also conducted during the study period.

Treatment groups were as shown in Table 1:

TABLE 1 Study 1 Design Surface Number Area Volume of Blood CollectionGroup Test Article Exposed Applied Animals Times (min) A 10% MSM + 90%Water 6 cm² 0.5 mL 1 0 (pre-dose), 10, 30, 120, 480 minutes B 50% DMSO +50% Water 6 cm² 0.5 mL 1 0 (pre-dose), 10, 30, 120, 480 minutes C 70%DMSO + 30% Water 6 cm² 0.5 mL 1 0 (pre-dose), 10, 30, 120, 480 minute D10% MSM + 50% DMSO + 6 cm² 0.5 mL 1 0 (pre-dose), 10, 30, 40% Water 120,480 minutes E 10% MSM + 70% DMSO + 6 cm² 0.5 mL 1 0 (pre-dose), 10, 30,20% Water 120, 480 minutes

One day prior to the experiment, the rump of each rabbit was closelyclipped using hair clippers. An area of 6 cm² was measured and marked toensure equivalence in the application of the various compositions. Eachproduct was applied by pipetting 0.5 mL of each composition into thecenter of the test area and spread to cover the entire test area. Afterthe 5 minute exposure period, the compositions were removed by wiping,rinsing and drying the test area.

Prior to blood collection, animals were tranquilized with Acepromazine(1 mg/kg) by intramuscular injection in the right hind leg muscle, afterwhich EMLA cream (lidocaine/prilocaine) was applied to both ears alongthe ear artery. Blood was collected by insertion of a 21G needle (hubremoved) into the ear artery. Approximately 2 mL of whole blood wascollected into 4 mL vacutainer™ tubes (Becton Dickinson, Mississauga,ON) containing K₂EDTA. Tubes were inverted to mix with the anticoagulantand stored refrigerated until plasma was separated by centrifugation.Plasma was separated from whole blood by centrifugation at 3000×g for 10minutes. Plasma was collected, transferred and stored in a cryovial at−70° C. until further processing for MSM analysis.

Following the 5 minute exposure period to the various test products (seeTable 1), blood was collected after 10 minutes, 30 minutes, 2 hours and8 hours. Prior to the 2 and 8 hour blood collections, EMLA cream wasapplied to the ears (approximately 30 minutes prior to each of theseblood draws) as the anesthetic effects of the EMLA cream lastsapproximately 1-2 hours. Both EMLA cream and Acepromazine were used dueto ethical considerations and to provide for the well being of theanimals used in this project.

The concentrations of MSM in plasma were quantified by GasChromatography-Mass Spectrometry (GC/MS) based on established methods.Briefly, 450 μL of plasma sample was mixed with 50 μL of physiologicalsaline and vortexed for 30 seconds. Following this 1 mL of Acetonitrile(Fisher, HPLC grade) was added to the mixture. The solution was vortexedvigorously for 60 seconds and centrifuged at 2000 rpm for 5 minutes. 1μL of the clear supernatant was introduced to the GC/MS system (GC/MSQP20108 EI, Shimadzu, Kyoto, Japan). The analysis was performed on a8himadzu SHR5XLB column (0.25mm ID×length 30 m, film 0.25 um, Kyoto,Japan). The retention time of MSM was 6.1-6.3 minutes. MSM was detectedwith MS and m/z 79 (M+−15) was used for monitoring MSM ion SIM profiles.Helium gas was used as the carrier gas, head pressure was 0.25 kg/cm2,make-up gas was 30 ml/min, column temperature was 80° C., injectortemperature 120° C., separator temperature 200° C. and ion sourcetemperature 250° C. The ionization energy was 70 eV. An externalstandard graph was prepared with MSM dissolved in acetonitrile at thefollowing concentrations: 62.5 μg/ml, 31.3 μg/ml, 15.6 μg/ml, 7.8 μg/ml,3.9 μg/ml, 1.9 μg/ml, 0.98 μg/ml and 0.49 μg/ml. The MSM concentrationin plasma samples was calculated from the slope of the standard curve.The best fitted graph was linear with a R2 value of 0.998.

All animals were observed prior to the start of the experiment and alldemonstrated good health. During the course of the experiment andsubsequent to the experiment, all animals demonstrated good health.Morbidity, mortality and injury were assessed twice daily. No animalsdemonstrated any morbidity, mortality or injury.

The results of the absorption study are summarized in Table 2 andgraphically depicted in FIGS. 1 and 2. Baseline plasma concentrations ofMSM (prior to exposure to test articles) ranged between 4.2 μg/mL and104.2 μg/mL (see FIG. 1). The variation in baseline is within the normalrange of variation of natural MSM concentrations that have beenestablished in prior studies. Following exposure to the various testarticles, the highest plasma concentrations of MSM measured were lessthan or equal to approximately 140 μg/mL (see FIG. 1). This peakconcentration results from exposure to 10% MSM+70% DMSO+20% water. Whencorrected for natural variation in baseline MSM concentrations, thelargest change in plasma MSM was detected in the 70% DMSO+30% watergroup. These data suggest that variations in MSM, either due toabsorption or due to metabolism of DMSO, are within the natural range ofMSM concentrations.

As such, in several embodiments, MSM is an inert ingredient in topicalapplications, with respect to analgesic function. However, as discussedherein, MSM does provide several beneficial effects. In severalembodiments, MSM functions to reduce the side effects normallyassociated with DMSO (skin effects, odor, etc.). In several embodiments,MSM functions as an emollient, which also may aid in reducing irritationof the skin by DMSO. As such, the combination of MSM with DMSO in thetopical formulation embodiments described herein allow for the use ofconcentrations of DMSO that function to reduce one or more symptoms ofosteoarthritis without the normal array of DMSO-associated side effects.Thus, in certain embodiments, the presence of MSM advantageously allowsfor the unexpected use of higher (and more efficacious) concentrationsof DMSO without the side effects.

TABLE 2 Concentration of MSM in Plasma After Exposure to MSM and DMSOTime point MSM Concentration Treatment (minute) (μg/mL) 10% MSM + 90%water 0 25.6 10 17.6 30 16.3 120 14.0 480 15.4 50% DMSO + 50% water 04.2 10 6.9 30 6.9 120 7.4 480 12.6 70% DMSO + 30% water 0 56.7 10 89.030 98.9 120 128.7 480 120.2 10% MSM + 50% DMSO + 0 104.2 40% water 10116.5 30 127.9 120 128.4 480 140.4 10% MSM + 70% DMSO + 0 26.8 20% water10 37.3 30 30.9 120 33.9 480 44.4

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe embodiments of the present invention. Method steps described hereinneed not be performed in the order set forth. It should be clearlyunderstood that embodiments disclosed herein are illustrative only andare not intended to limit the scope of the present invention.

What is claimed is:
 1. A solid oral formulation comprisingdimethylsulfoxide (DMSO) and methylsulfonylmethane (MSM) as prills,microprills, or flakes, wherein the prills, microprills, or flakes (a)are prepared by flacking, prilling and/or freezing a liquid combinationof DMSO and MSM, and (b) stay solid at room temperature.
 2. The solidoral formulation of claim 1, comprising about 5 mg to about 50 mg DMSO.3. The solid oral formulation of claim 2, comprising about 300 mg toabout 800 mg MSM.
 4. The solid oral formulation of claim 1, comprisingabout 30 mg to about 50 mg DMSO and about 500 mg to about 800 mg MSM. 5.The solid oral formulation of claim 1, wherein the liquid combination isprepared by heating a combination of liquid DMSO and solid MSM.
 6. Thesolid oral formulation of claim 1, wherein the prills, microprills, orflakes have a diameter of about 75 microns to about 840 microns.
 7. Amethod for reducing inflammation or pain in a human subject in needthereof, comprising orally administering to the human subject a solidoral formulation of claim
 1. 8. The method of claim 7, where the oraladministration reduces chronic inflammation or pain and reducesosteoarthritis.
 9. A method of reducing inflammation or pain in a humansubject in need thereof, comprising topically administering to the humansubject a topical formulation comprising about 65-70% v/vdimethylsulfoxide (DMSO) and about 25-35% v/v methylsulfonylmethane(MSM), wherein the topical formulation is provided in a gel, cream,serum, liquid, spray, ointment, and/or patch form.
 10. The method ofclaim 9, wherein the topical formulation is administered at a hand, aknee or another joint.
 11. The method of claim 9, wherein the topicalformulation is administered at a hand.
 12. The method of claims 9,further comprising orally administering to the human subject a solidoral formulation comprising DMSO and MSM as prills, microprills, orflakes, wherein the prills, microprills, or flakes (a) are prepared byflacking, prilling and/or freezing a liquid combination of DMSO and MSM,and (b) stay solid at room temperature.
 13. The method of claim 9,wherein the topical administration provides acute relief of pain andinflammation.